Question

In this chapter, we focused on cancer as a genetic disease. In particular, we discussed the relationship between cancer, the cell cycle, and mutations in proto-oncogenes and tumor-suppressor genes. Based on your knowledge of these topics, answer several fundamental questions: (a) How do we know that malignant tumors arise from a single cell that contains mutations? (b) How do we know that cancer development requires more than one mutation? (c) How do we know that cancer cells contain defects in DNA repair?

Short answer

Question: Explain the genetic basis of cancer, including the origin of malignant tumors, the requirement of multiple mutations, and the presence of defects in DNA repair. Answer: The genetic basis of cancer involves the accumulation of mutations in key genes, leading to uncontrolled cell growth and division. Malignant tumors originate from a single mutated cell that undergoes clonal expansion, forming a population of cells with the same genetic alterations. Cancer development requires more than one mutation, as supported by the multiple-hit hypothesis, which proposes that successive mutations lead to progressively severe cellular abnormalities. Defects in DNA repair mechanisms are also common in cancer cells, resulting in a higher rate of mutations and further contributing to the development of cancer.

Step-by-step solution

a) How do we know that malignant tumors arise from a single cell that contains mutations?

To answer this question, we need to understand the concept of clonal expansion. When a single mutated cell divides uncontrollably and accumulates additional mutations, it forms a population of cells with the same genetic alterations, called a clone. The malignant tumor that arises from this process is derived from these clones. Evidence supporting the idea that tumors arise from a single mutated cell includes: - Tumors usually display genetic homogeneity, meaning that their cells have similar mutations and genetic markers. - Experiments have shown that injecting a single cancerous cell into an organism can cause the formation of a tumor. - The process of tumorigenesis is a stepwise process, with the accumulation of mutations driving the progression from a benign tumor to a malignant one.

b) How do we know that cancer development requires more than one mutation?

The development of cancer is a complex, multi-step process. It has been observed that not all cells with certain mutations progress to cancer, indicating that multiple mutations are required for full malignant transformation. Additionally, the process of tumorigenesis shows a general pattern in which successive mutations lead to increasingly severe cellular abnormalities. This concept is known as the multiple-hit hypothesis in cancer development. Evidence for the requirement of more than one mutation in cancer development includes: - The fact that cancer incidence rates increase with age, which correlates with the time required for the accumulation of multiple mutations. - Observations of multistage carcinogenesis in experimental models, such as the conversion of normal cells to malignant ones with sequential genetic alterations. - Identification of proto-oncogenes and tumor-suppressor genes, both of which can contribute to cancer development when mutated, and their mutations are usually found together in cancer cells.

c) How do we know that cancer cells contain defects in DNA repair?

Cancer cells often have a higher rate of mutations than normal cells, which can be attributed to defects in their DNA repair mechanisms. DNA repair is crucial for maintaining the integrity of genetic material when it gets damaged. Many studies have shown that defects in DNA repair pathways contribute to the accumulation of genetic changes in cancer cells. Evidence for defects in DNA repair in cancer cells includes: - Mutations in genes responsible for DNA repair are often found in cancer cells, suggesting that these defects play a role in tumorigenesis. - People with inherited deficiencies in DNA repair genes have higher cancer risks than those without these deficiencies. - DNA repair deficient cells have been shown to become cancerous more easily when exposed to carcinogens that induce DNA damage. In conclusion, understanding the genetic basis of cancer helps us to answer fundamental questions about its development, such as the origin of malignant tumors, the requirement of multiple mutations, and the presence of defects in DNA repair.

Key concepts

Cell Cycle

The cell cycle is the series of events that lead to cell division and duplication. It is crucial for growth, repair, and maintenance in organisms. Understanding the cell cycle is key to comprehending how cancer develops, as cancer is fundamentally a disease of cell cycle control. Normal cells follow a regulated cell cycle, but cancer cells bypass these controls, leading to uncontrolled growth.
The cell cycle consists of several phases:

• G1 phase (Gap 1): The cell grows and carries out regular functions. It prepares for DNA synthesis.
• S phase (Synthesis): DNA is replicated so that both daughter cells will have a copy.
• G2 phase (Gap 2): The cell prepares for mitosis, checking for any DNA errors.
• M phase (Mitosis): The actual division of the cell into two daughter cells.
• Checkpoint Controls: Cells have mechanisms in place that monitor and verify each phase before moving forward.

When these checkpoints fail, due to mutations or other factors, cells undergo uncontrolled division, often leading to cancerous growths.

Proto-Oncogenes

Proto-oncogenes are normal genes that play critical roles in normal cell growth and division. They act like the gas pedal of a car, driving the cell cycle forward. Through mutations or increased expression, these genes can become oncogenes, which contribute to cancer progression.
Transformation into oncogenes can occur due to:

• Point Mutations: A change in a single nucleotide, altering the function of the protein product.
• Gene Amplification: Increase in the number of copies of a proto-oncogene, leading to overexpression.
• Chromosomal Translocation: Parts of a chromosome are rearranged, affecting gene placement and function.

Oncogenes serve as a key player in the onset and progression of cancer by promoting cell growth and division without proper regulation, often in conjunction with other mutated genes.

Tumor Suppressor Genes

Tumor suppressor genes are the brakes of cell division, preventing cells from growing uncontrollably. When functioning properly, they inhibit cell division, repair DNA mistakes, or trigger cell death if errors are irreparable.
Mutations in these genes can lead to cancer by removing these protective mechanisms, akin to removing the brakes from a vehicle.
Key features of tumor suppressor genes include:

• Recessive Nature: Often, both alleles (gene copies) must be affected by mutations for the loss of function.
• Examples: Well-known tumor suppressors include genes like p53, RB1 (Retinoblastoma), and BRCA1.
• DNA Repair and Apoptosis: Some specifically manage DNA repair and initiating apoptosis (programmed cell death) to prevent the propagation of damaged DNA.

Mutations often occur in conjunction with the activation of oncogenes, which can further accelerate the development of cancer.

Clonal Expansion

Clonal expansion refers to the process where a single cell, often with a genetic mutation, replicates and forms a clone, or a group of identical cells. This is foundational in the development of cancer, starting with one mutated cell that, when not controlled, leads to tumor formation.
Steps involved in clonal expansion include:

• Initial Mutation: A single-cell undergoes a mutation that gives it growth advantages.
• Uncontrolled Division: The mutated cell bypasses normal regulatory checkpoints.
• Formation of a Clone: Repeated cell divisions form a population of genetically similar cells.

A visible tumor may form if the clone undergoes further mutations that allow evasion from immune detection, increased growth, or resistance to apoptosis. Clonal expansion links the genetic mutation to physical tumor formation, illustrating how cancer progresses from initial errors to impactful disease.

DNA Repair Defects

DNA repair mechanisms are essential for maintaining genomic stability. They correct DNA damages that occur from environmental factors or errors in replication.
Deficiencies in these systems can lead to increased mutation rates, as unrepaired DNA can accumulate mutations that potentially initiate cancer.
Critical aspects of DNA repair defects include:

• Mechanisms: Includes base-excision repair, nucleotide-excision repair, and mismatch repair.
• Inherited Syndromes: Conditions like Lynch syndrome and Xeroderma Pigmentosum show increased cancer risk due to inherited DNA repair defects.
• Genomic Instability: Cells with repair defects have a higher likelihood of accumulating genetic alterations over time, a common feature in cancer cells.

Defective DNA repair pathways contribute to the higher mutation burden seen in cancer types, acting as a catalyst for the multifaceted mutations required for cancer progression.